This invention was made in the course of research sponsored by the National Institutes of Health. The U. S. Government may have certain rights in this invention.
This invention relates to newly identified polynucleotides and polypeptides, and their production and uses, as well as their variants, agonists and antagonists, and their uses. In particular, the invention relates to polynucleotides and polypeptides of the AAC-11 (antiapoptosis clone-11) family, hereinafter referred to as xe2x80x9cAAC-11xe2x80x9d.
Programmed cell death, or apoptosis, plays a critical role in development, tissue renewal and repair, and tumor growth (Thompson. C.B. Science 1995, 267:1456-1462; Stewart, B. W. J. Natl. Cancer Inst. 1994, 86:1286-1296). Apoptosis may be induced directly by a host of physiological or nonphysiological signals including tumor necrosis factor, FAS ligand, oxidative stress, and viruses. Alternatively, apoptosis occurs after removal of extracellular growth factors, cytokines, or attachment substrata or by the inappropriate expression of cell cycle components. The latter observations suggest that apoptosis in proliferating cells reflects a conflict in the cell cycle or a default pathway in cell cycle progression that is diverted by specific intracellular factors (Evan et al. Curr. Opin. Cell Biol. 1995, 7:825-834; Meikrantz, W. and R. Schlegel J. Cell. Biochem. 1995, 58:160-174). Viewed differently, cellular viability is dependent on the functional balance of factors that favor apoptosis versus extracellular (e.g., growth factors) and intracellular survival signals. Examples of such survival factors include bcl-2 and related family members (Yang, E. and S. J. Korsmeyer Blood 1996, 88:386-401), proteins that inhibit tumor necrosis factor killing such as MnSOD (Wong et al. Cell 1989, 58:923-931), A20 (Opipari et al. J. Biol. Chem. 1992, 267:12424-12427), and plasminogen activator inhibitor 2 (Kroemer et al. FASEB J. 1995, 9:1277-1287; Dickinson et al. J. Biol. Chem. 1995. 270:27894-27904), as well as recently identified proteins such as calcium-binding protein ALG-2 (Vito et al. Science 1996, 271:521-525) and mammalian homologues of baculovirus IAP gene (Liston et al. Nature 1996, 379:349-353; Hay et al. Cell 1995, 83: 1253-1262; Duckett et al. EMBO J. 1996, 15:2685-2694).
Many growth factors and cytokines act as cellular survival factors by preventing apoptosis. However, the specific genes and corresponding proteins that mediate cell survival are poorly defined. For example insulin-like growth factor I (IGF-I) prevents apoptosis in diverse settings, including deprivation of growth factors and cytokines (Barres et al. Cell 1992, 70:31-46; Rodriguez-Tarduchy et al. J. Immunol. 1992, 149:535-540), cell cycle dysregulation (Harrington et al. EMBO J. 1994, 13:3286-3295; Sell et al. Cancer Res. 1995, 55:303-306), ischemia (Buerke et al. Proc. Natl. Acad. Sci. USA 1995, 92:8031-8035), administration of tumor necrosis factor, hyperosmotic shock (Matthews. C. C. and Feldman. E. L. J. Cell Physiol. 1996, 166:323-331), and activation of IL-lb-converting enzyme (Yong-Kuen et al. J. Biol. Chem. 1996, 271:5112-5117). However, the mechanism by which the activated IGF-I receptor inhibits apoptosis is unknown. For growth factor-regulated cells such as murine fibroblasts, long-term survival in the presence of IGF-I does require continuous gene expression (Tamm, I. and Kikuchi, T. J. Cell. Physiol. 1990, 143:494-500). IGF-I modulates gene expression both transcriptionally and for survival by stabilizing existing mRNA transcripts (Zumstein, P. and Stiles C. D. J. Biol. Chem. 1987 262:11252-11260).
In a more recent publication by Ambrosini et al., a new anti-apoptosis gene referred to as xe2x80x9csurvivinxe2x80x9d is disclosed (Ambrosini, G. et al. Nat. Med. 1997. 3:917-921). This gene encodes a 16.5 kDa protein and is found in more than 50% of non-Hodgkin""s lymphomas examined. The mRNA detected was 1.9 kb.
A novel cDNA has now been isolated and is referred to herein as antiapoptosis clone 11 (AAC-11). This clone expresses a 25 kDa protein that prevents apoptosis caused by deprivation of growth factors in a cell.
The present invention relates to AAC-11 in particular AAC-11 polypeptides and AAC-11 polynucleotides, recombinant materials and methods for their production. In another aspect, the present invention relates to methods for using such polypeptides and polynucleotides, including methods of inhibiting apoptosis in a cell. In a further aspect, the present invention relates to identifying agonists and antagonists using the materials provided by the invention. In still a further aspect, the present invention relates to compositions and methods for inhibiting apoptosis in a cell, preferably an animal cell, most preferably a human cell. In another aspect, the present invention relates to a method of inhibiting apoptosis in a cell, preferably an animal cell, most preferably a human cell, wherein an effective amount of a protein encoded by a AAC-11 polynucleotide so that apoptosis in the cell is inhibited. In another aspect, the present invention relates to a method of inhibiting apoptosis in a cell, preferably an animal cell, most preferably a human cell, wherein an effective amount of a AAC-11 polynucleotide is administered to the cell so that the cell encodes the polynucleotide thereby inhibiting apoptosis in the cell. In yet a further aspect, the present invention relates to compositions and methods for inducing apoptosis in a cell by inhibiting expression of the AAC-11 polynucleotides or the activity of the AAC-11 polypeptides encoded thereby.